CN1093708A - Pyrrole derivative - Google Patents
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- CN1093708A CN1093708A CN93121279A CN93121279A CN1093708A CN 1093708 A CN1093708 A CN 1093708A CN 93121279 A CN93121279 A CN 93121279A CN 93121279 A CN93121279 A CN 93121279A CN 1093708 A CN1093708 A CN 1093708A
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- 0 CC(C=[C@]=C(*=C(C)N)C(CCC*1CCOCC1)=C)=C Chemical compound CC(C=[C@]=C(*=C(C)N)C(CCC*1CCOCC1)=C)=C 0.000 description 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
2-(2-furyl)-5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine and pharmacy acceptable salt thereof be A optionally
2The a adenosine antagonist.The medicinal compositions that contains this compound and their preparation method are also disclosed in addition.
Description
The present invention relates to new pyrrole derivative, more particularly, relate to new 2-heteroaryl triazolo [1,5-a] [1,3,5] triazine and pharmacy acceptable salt thereof, it has useful pharmacological property (the particularly effect of antagonism adenosine is as vasorelaxation action).This invention also comprises the medicinal compositions of the new pyrrole derivative that contains the disease that can be used for treating infringement mammalian heart, periphery and/or cerebrovascular system, also comprises the production method of this new pyrrole derivative.
It is stimulant, bronchodilator, cardiostimulator and the diuretic(s) of respiratory stimulant, central effect that compound theophylline (1, the 3-dimethyl xanthine) is used (be generally its ethylenediamine salt, be also referred to as aminophylline) clinically.The diversity of clinical application is the indication of theophylline pharmacological action scope just.They comprise the moving and the release of catecholamine of antagonistic action, intracellular Ca2+ of restraining effect, the Adenosine Receptors of phosphodiesterase.Report in addition that recently theophylline can be used for treating myocardial ischaemia (Maseri etc., The Lancet, 1989,683-686), skeletal muscle local asphyxia (Picano etc., Angiology, 1989,40,1035-1039) and cerebral ischaemia (Skinhoj etc., Acta.Neurol.Scand., 1970,46,129-140).It is believed that useful effect just is that it can reduce or prevent to be called as the phenomenon of " blood vessel is stolen blood " (" vascular steal ") to theophylline to these ischemic diseases.Its this effect is that described Adenosine Receptors can be regulated the vasodilation relevant with metabolism because thereby this compound can be blocked the effect of Adenosine Receptors antagonism adenosine.
When the aorta of supply particular blood vessel bed is partly or entirely blocked and will occur the phenomenon of " blood vessel is stolen blood " when causing local asphyxia.In this case, impaired vescular bed expands, and keeping of volume of blood flow is to finish by the volume of blood flow increase of the blood vessel that narrows down or by the volume of blood flow increase of collateral blood vessels.But the metabolic activity of adjacent blood vessel bed strengthens, and can cause the release of the medium resemble the theophylline, and these vescular beds are expanded, and causes reducing because of " being stolen " by contiguous blood vessel institute by the blood volume of damaged blood vessels bed.The phenomenon of " blood vessel is stolen blood " is injected on the normal vescular bed blood that loses from the damaged blood vessels bed, and then reduces the volume of blood flow of damaged blood vessels bed.
The diversity of the pharmacological property that theophylline had makes it be difficult to the conventional treatment or the prevention of infraction property disease and vascular system illness.Therefore, its dependent interaction as phosphodiesterase inhibitor causes the heart excitement, and this patient to myocardial ischaemia is deleterious.In addition, the theophylline potency is lower, and the effective dosage of its treatment has approached to cause the dosage of serious central nervous system-mediated side effects in other words.
European patent application (publication number EP-A1-459702) discloses some 2-heteroaryl triazolo [1,2,4] triazolo [1,5-a] [1,3,5] triazine and pyrazolo [2,3-a] [1,3,5] triazine, they are effective antagonists of effective antagonist of gland glycoside action, particularly its vasorelaxation action.
Have now found that 2-heteroaryl triazolo [1,2,4] triazolo [1,5-a] [1,3,5] triaizine compounds has special valuable pharmacological characteristic.
Therefore, the invention provides compound 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine and pharmacy acceptable salt thereof.
The compounds of this invention can be represented with the formula I, and together represent with Roman number with other related formula of this paper hereinafter.The compounds of this invention will be known as formula I compound hereinafter.
Discoverable type I compound is the selective antagonist of adenosine on the adenosine A 2a acceptor.This is subjected to physical efficiency to regulate the vasorelaxation action of adenosine.It is good especially water-soluble and in vivo by oral and the parenteral route administration is all very effective, astonishing to find that also this compound has.The combination of several specific characters caters to the need unexpectedly and especially.
The pharmacy acceptable salt of concrete formula I compound comprises: for example with the salt that the acceptable anionic acid formation of physiology can be provided, for example with following sour salt example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoroacetic acid, oxalic acid, citric acid and the toxilic acid that forms.
On the other hand, the invention provides the preparation method of formula I compound or its pharmacy acceptable salt, it comprises: (a) with formula II compound and N-(2-amino-ethyl) morpholine or its reactant salt; In the described formula II compound, Z is suitable leavings group such as alkyl alkylsulfonyl for example (1-6C) alkyl sulphonyl (as methylsulfonyl or ethylsulfonyl), aryloxy such as phenoxy group or halogeno-group (halogen) (as chloro base or bromo base).
This reaction can be carried out as 10-80 ℃ in 0-120 ℃ of temperature range.The solvent that is fit to this reaction comprises nitrile such as acetonitrile, and is pure as ethanol or propyl alcohol, ether such as tetrahydrofuran (THF), 1,2-glycol dimethyl ether or uncle's fourth methyl ether and acid amides such as N, dinethylformamide.
The N-(2-aminoethyl) salt of morpholine has for example an alkali metal salt such as lithium salts, sodium salt and sylvite.
Just can obtain formula II reactant by the described method of EP-A1-459702.So for example Z is that the formula II compound of alkyl sulphonyl can be by the corresponding formula III of oxidation alkylthio derivative [R in the formula in those formulas
1Be (1-6C) alkylthio] obtain; This reaction usefulness be common oxygenant such as peracetic acid, peroxybenzoic acid or chlorine peroxybenzoic acid as peracid, this reaction is carried out in 0-40 ℃ temperature range for example and in suitable solvent or thinner such as methylene dichloride or the chloroform usually.Equally, hydrogenchloride is being arranged respectively, or under the condition that exists of hydrogen bromide, in the ordinary temp scope as-20-15 ℃ and in inert polar solvent such as ethanol or 2-propyl alcohol usually, formula III alkylthio derivative (especially, R in the formula
1Be methylthio group or ethylmercapto group) and the chlorine or bromine reaction can obtain, and Z is the formula II compound of chlorine or bromine in the formula.
Initial formula III alkylthio reactant itself can for example be made by following reaction: formula IV compound and suitable formula V N-cyano group dithio iminocarbonic acid dialkyl at the temperature range internal reaction of high temperature as 60 ℃ to 200 ℃, are preferably the melts form under the condition of solvent-free and thinner.
Under the situation of the suitable alkali that also can be used as reaction solvent such as pyridine or lutidine existence, in 60-120 ℃ of temperature range for example, formula IV initial compounds itself can be for example by an amount of formula Q.C(OR)=NH imino-ether and aminoguanidine salt (particularly nitrate) reaction obtain; Described formula Q.C(OR)=the NH imino-ether in, Q is that 2-furyl and R are (1-4C) alkyl such as methyl or ethyl (this imino-ether is under the condition that anhydrous acid such as hydrogenchloride exist, and is generated by corresponding formula Q.CN nitrile and formula R.OH alcohol).
With 5,7-two phenoxy groups-[1,2,4] triazolo [1,5-a] [1,3,5] triazine and ammonia react can make formula II compound (Z is a phenoxy group in the formula) easily.This process should be carried out in 0-100 ℃ of temperature range.The solvent that is fit to this process comprises alcohol as ethanol and ether such as tetrahydrofuran (THF), the suitable especially alcoholic solution of ammonia such as the ethanolic soln of ammonia used at ambient temperature.
The formula VI compound dehydration that each Z is the phenoxy group group just can obtain 5,7-two phenoxy groups-[1,2,4] triazolo [1,5-a] [1,3,5] triazine reactant.The dewatering agent that is fit to comprises for example Tripyrophosphoric acid silyl ester such as Tripyrophosphoric acid trimethylsilyl group, Vanadium Pentoxide in FLAKES and SULPHURYL CHLORIDE such as Tosyl chloride.Dehydration should be carried out in 60-180 ℃ of temperature range.When using Tripyrophosphoric acid silyl ester or Vanadium Pentoxide in FLAKES, The suitable solvent comprises aromatic hydrocarbons such as dimethylbenzene or toluene.When using SULPHURYL CHLORIDE, The suitable solvent comprises tertiary amine such as pyridine.
Formula VII compound cotype QCOHal compound (Hal is halogen atom such as chlorine atom in the formula) reaction that each Z in the formula is the phenoxy group group can obtain formula VI compound.This reaction should be carried out in-10-40 ℃ temperature range.This reaction The suitable solvent comprises halohydrocarbon such as methylene dichloride.
Formula VIII compound (Z is the phenoxy group group in the formula) and hydrazine reaction can obtain formula VII compound.
Perhaps, formula VI compound can through type in each Z be the formula VIII compound and the formula QCONHNH of phenoxy group group
2The compound reaction makes.
In addition, the invention provides another preparation method of formula I compound or its pharmacy acceptable salt, it comprises:
(b) formula IX compound is reacted Z in the described formula IX with morpholine
1Represent suitable leavings group, for example alkyl sulfonyloxy (as tolysulfonyl oxygen base) or halogeno-group (as chloro base or bromo base).
This method should for example implemented in 10-120 ℃ of temperature range, more suitablely implements in 30-80 ℃ of temperature range.The suitable solvent of this reaction comprises for example pure as ethanol, nitrile such as acetonitrile, acid amides such as N, dinethylformamide and ether such as tetrahydrofuran (THF), 1,2-glycol dimethyl ether and uncle's fourth methyl ether.
Formula IX reactant can be obtained Z in the described formula IX by corresponding formula IX compound with standard method well known in the art
1It is hydroxyl.This compound itself can be according to the method for above-mentioned steps (a), prepares by formula II compound and 2-monoethanolamine are reacted.
In addition, the invention provides another preparation method of formula I compound or its pharmacy acceptable salt, it comprises:
(c) with formula X compound and ammonia react, the Z in the described formula X
2Represent for example aryloxy (as phenoxy group) of suitable leavings group, alkylthio (as methylthio group) or halogeno-group (as chloro base or bromo base).
This reaction should for example carried out in 0-100 ℃ of temperature range, and the solvent of suitable this reaction comprises water, and alcohol is as ethanol and ether such as tetrahydrofuran (THF).
The dehydration of formula XI compound can be obtained formula X reactant.Suitable dewatering agent comprises for example Vanadium Pentoxide in FLAKES, Tripyrophosphoric acid silyl ester such as Tripyrophosphoric acid trimethylsilyl group or SULPHURYL CHLORIDE such as Tosyl chloride.Dehydration should be carried out in 60-180 ℃ of temperature range.When using Vanadium Pentoxide in FLAKES, The suitable solvent comprises aromatic hydrocarbons such as dimethylbenzene or toluene.When using SULPHURYL CHLORIDE, The suitable solvent comprises tertiary amine such as pyridine.
Formula VI compound and N-(2-aminoethyl) morpholine reaction can obtain formula XI compound.
In addition, the invention provides another preparation method of formula I compound or its pharmacy acceptable salt, it comprises:
(d) formula XII compound is dewatered
Suitable dewatering agent comprises for example Tripyrophosphoric acid silyl ester such as Tripyrophosphoric acid trimethylsilyl group, Vanadium Pentoxide in FLAKES and SULPHURYL CHLORIDE such as Tosyl chloride.Dehydration should be carried out in 60-180 ℃ of temperature range.When using Tripyrophosphoric acid silyl ester or Vanadium Pentoxide in FLAKES, The suitable solvent comprises aromatic hydrocarbons such as dimethylbenzene or toluene.When using SULPHURYL CHLORIDE, The suitable solvent comprises tertiary amine such as pyridine.
Formula XII reactant can be by any easy program by formula VIII compound and ammonia, N-(2-aminoethyl) morpholine and 2-furoyl hydrazine reaction obtain.
Then, if will obtain pharmacy acceptable salt, can for example make formula I compound and acid or the alkali reaction that physiologically acceptable ionic is fit to can be provided or utilize other usual way and obtain.
As mentioned above, The compounds of this invention has the character of one or more physiological actions of antagonism adenosine, to the mammiferous heart, on every side and/or the disease of maincenter vascular system such as ischemic heart disease (stenocardia), peripheral vascular disease (limping) and cerebral ischaemia all have therapeutic action.This compound also can be used for treating migraine.
Formula I compound can be confirmed in the external and/or in vivo test of one or more following standards as the effect of adenosine receptor antagonists.
(a) A
2The test of a Adenosine Receptors avidity
This test relate to tested adenosine antagonist from the combining site on the cytolemma goods replace known adenosine imitate agent [
3H]-ability of N-ethyl-formamide base adenosine (NECA).Described cytolemma goods prepare from rat brown pigments glucagonoma (phaeochromocytoma) clone PC12, (can obtain) from Beatson institute (Glasgow), Williams etc. is seen in the elementary operation of test, J.Neurochemistry, 1987,48(2), 498-502.
Membrane product can obtain as follows:
Frozen sheeted throw out with ice-cold buffer saline flushing PC12 cell, and obtain cell with centrifuging (1500G) in 3 ℃, then isolated cells is suspended in the hypotonic solution (distilled water), and be placed on and leave standstill 30 minutes on ice, use the careful homogenizing of high speed homogenizer of standard then, carry out periodically ice-coldly simultaneously, obtain very thin suspension liquid.With this equal one centrifugal (48000G), and with this pellet resuspending in the pH value is 7.4 50mM tris-HCl damping fluid, (5 units per ml, VII type obtain from the calf casing slime to contain the adenosine deaminase in this damping fluid; Sigma chemical company produces, referring to A1280 number).Then with this mixture constant temperature in 37 ℃.After 20 minutes, this reaction is finished with ice-cold damping fluid dilution, and with its dislocation on ice.With the material that contains cytolemma that obtains through centrifugal recovery, and by with its resuspending in centrifugal again flushing of damping fluid neutralization.Then with manual homogenize machine with the flap resuspending that makes in ice-cold damping fluid, this film suspension that obtains is freezing and to place liquid nitrogen to preserve stand-by.
In conjunction with research is what to carry out on microtiter plates under the condition of room temperature and pH7.4, and this is measured mixture and is buffered among the 50mM tris-HCl.Test compound is dissolved in the methyl-sulphoxide (DMSO), [the final concentration of DMSO can not surpass 1% of volume to obtain testing liquid with the dilution of mensuration damping fluid then, in this limit, can not influence the radioligand that is attached on the membrane receptor], in cumulative volume 150 μ l in 30 ℃ of constant temperature 90 minutes, comprise testing liquid or damping fluid (50 μ l) in the described cumulative volume, the NECA(50 μ l of tritiate) and film suspension liquid (50 μ l).Behind the constant temperature, sample is used the glass fibre beam filter rapidly, wash this fibrous bundle to remove the radioligand of non-receptors bind.The radioligand that retention is the receptors bind in the fibrous bundle is measured with liquid scintillation counting(LSC) then.Filter and wash by using conventional vacuum apparatus to finish.
Carrying out specificity in the presence of concrete test compound measures in conjunction with (being defined as the poor of total combination and non-specific binding) and compares with control value.The result replaces the negative logarithm (pIC of the specificity of contrast in conjunction with required concentration with producing 50%
50) express easily.
The pIC of this paper embodiment 1 compound
50Be 7.6.Utilize same testing method, known compound 1, the pIC of 3-dimethyl xanthine
50Generally be about 5.
(b) cavy room bradycardia test
(British J.Pharmacology such as the also visible Collis of this test, 1989,97,1274-1278), it relates in dancing guinea-pig atrial sample test compound to the antagonistic ability of the bradycardia effect of intending adenosine-2-chlorine adenosine with to by being referred to as A
1The antagonistic ability of the effect that Adenosine Receptors is regulated.
The atrium (to) sample can press method preparation:
The atrium (to) derive from cavy (Dunkin Hartley strain, body weight 250-400g, male) and be fixed in 37 ℃ and contain by O
2(95%O in the organ bath of saturated Kreb ' s damping fluid
2; 5%CO
2).After spontaneous beating recovered in the atrium, make the quiet pulling force of its suspention 1g, and under the situation of continuous overflow, make its balance 50 minutes.Stop overflow then, add adenosine deaminase (1 unit/ml) accumulate with the adenosine that prevents atrium endogenous generation.After the balance 15 minutes, give adenosine simulant-2-chlorine adenosine (10
-8M-10
-4M), the dose response curve of atrium to this simulant calculated in accumulation, so that the degree that slows down of AR is reached maximum.Continuously flushing is after 30 minutes, adds adenosine deaminase and balance 15 minutes to bath once more.With 10 of test compound
-5M DMSO solution adds in the bath, and cultivates 30 minutes.Before the dose response curve of replication, should note causing beat any influence of the rhythm and pace of moving things of atrium by test compound to 2-chlorine adenosine.The adenosine antagonist compound can weaken the reaction of 2-chlorine adenosine.
Test compound can be by the atrium to single dose response curve and relatively the estimating of the dose response curve that obtained in the presence of this compound with 2-chlorine adenosine.Competitive adenosine antagonist produces parallel moving in 2-chlorine adenosine dose response curve.By when having test compound to exist, each atrium being caused that AR reduces 50%(ED
50) the ED of concentration 2-chlorine adenosine when not having test compound to exist of 2-chlorine adenosine
50The ratio of concentration calculate the ratio of dosage.Calculate pA with standard computer programs then
2The pA of this paper embodiment 1 compound
2Be 5.5.Known compound-1, the pA of 3-dimethyl xanthine
2Generally be about 5.
If the pA of embodiment 1 compound that will in this test, obtain
2The pIC of value and same a kind of compound of in this test (a), obtaining
50Compare, we as can be seen this compound to A
2aThe selectivity of acceptor is higher than A
1Acceptor is more than 100 times.This especially caters to the need, because at A
1The antagonistic action of the adenosine on the acceptor can have influence on kidney, adipocyte, heart and central nervous system.
(c) anesthesia dog experiment
This experiment is the evaluation that adenosine is reduced the heart rate and the antagonistic action of the effect that increases vasodilation (by measuring the decline of hind leg injection pressure) about test compound.
Anaesthetize than brother hunting dog (12-18kg) with vetanarcol (50mg/kg, quiet notes).In following blood vessel, insert conduit: right jugular vein (being used for per hour injecting the about 112mg of narcotic that exists with 3mg/ml normal isotonic saline solution form), right arm vein (being used for) to medicine and test agent, right brachiocephalic artery (being used for the measuring body blood pressure and pulse) and left neck artery (being used for adenosine is injected left ventricle).To cut off after vagus nerve and right femur and the whole ligation of sciatic nerve.Before using iliac artery blood with the blood perfusion right lower extremity that continues, the heparin of bolus injection 1250 units.With of the downside ligation of right leg at adjacent ankle joint.Give animal xamoterol (Xamoterol) then (1mg/kg), the heart rate stabilization that makes animal is at high level, and gives and nitrobenzyl NSC-40774 (NBTI 0.5mg/Kg) for the picked-up that suppresses adenosine.Give and NBTI after balance period between make animal to the adenosine sensitivity by carrying out dose response curve (DRC) mensuration.During this period, any imbalance of gas in the blood and pH all need be corrected.Mensuration is to the contrast DRC of adenosine, gives and is added in 50%(v/v in accumulation subsequently) behind the test compound in the mixture of polyoxyethylene glycol (PGE) 400 and 0.1M sodium hydroxide, carry out three DRC and measure.Give with test compound after and after heart rate and hind leg Ppa pulmonary artery pressure measuring parameter have been got back to steady state, carry out the mensuration 15 minutes of each DRC.Equally, in whole evaluation procedure, flood gas and pH all remain within the physiological range.
Each Rapid Dose Calculation to test compound can cause measuring parameter (ED
50) be heart rate and hind leg Ppa pulmonary artery pressure descend 50% required adenosine amount and draw Schild figure.From then on the K of figure
BValue is determined the antagonistic action to the heart rate response of adenosine and vasodilation reaction.With regard to the antagonistic action that the vasodilation of adenosine is reacted, found the K of embodiment 1 compound
BIn the 0.01-0.24mg/Kg scope, it is nontoxicity performance or other disadvantageous effect under greater than the dosage of several times of minimum effective doses.
(d) waking state cat blood pressure test
This test is the impedance of evaluation test compound owing to inject the ability of the diastolic pressure reduction that adenosine produced.
Select male cat (2-4.5Kg) and train them undisturbedly to sit in front in the box of opening.Prepare suitable animal then to be used for inserting for a long time conduit.Use the alphalaxone/ alphadrone) (18mg, quiet notes) induced anesthesia and keep anesthesia, delivery of supplemental oxygen with trifluoro bromochloromethane (1.5-3%).The back side and the belly of neck are clamped, used alcohol/Tubulicid/water (70/20/10%v/v) solution to clean then.Right carotid (being used to measure the systemic arterial blood pressure) and right jugular vein (being used to inject adenosine or substances) are inserted into conduit and external.Two conduits are sewn, and the edge of a knife is sealing also.Cat is sent back to respectively after clear-headed in their the former animal housing of living.Before these animals being used for experiment, to there be the postoperative recovery time in a week at least.
All surgical operations are all implemented with Aseptic technique.All utensils are all wanted high-temperature sterilization before using.Conduit will be immersed in before implantation in alcohol/liquor hibitane one hour at least, cleaned tissue necrosis to prevent that alcohol/liquor hibitane from causing with aseptic salt solution then.
Cat is separated to be positioned in the box of opened front, and is unrestricted.Behind the short-term regulation, to the adenosine of the selected dosage (siting dose) of 0.6mg/kg, with the susceptibility of evaluation cat to adenosine.Continuous three bolus injection adenosines, dosage are respectively 0.6,1.0 or 1mg/kg, and measure the reduction of diastolic pressure.Use test compound to cat then,, perhaps be used for intravenous injection with the solution form perhaps with the solid of this compound or be dissolved in the solution that polyoxyethylene glycol (PEG) 400 makes and give cat oral.
Give and test compound after 15 minutes and 24 hours between repeat adenosine and attack.The activity of test compound is to represent the inhibition percentage of diastolic blood pressure reaction.Find the significant adenosine antagonist activity of embodiment 1 compound tool when dosage is 0.3-1mg/Kg, and under the several times dosage of minimum effective dose, do not seen any tangible toxicity performance.
The compounds of this invention preferably uses to reach the purpose of treatment and prevention to warm-blooded animal with the form of medicinal compositions usually, its objective is treatment or preventing cardiovascular disease; Described composition contains described formula I compound or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.Such composition also is another feature of the present invention.
In general, but expectation formula I compound oral administration, quiet notes or other medically acceptable approach are (as sucking, be blown into, hypogloeeis or endermic means) use, total dosage range is acceptable in for example 0.001-10mg/Kg body weight (or more particularly, in the scope of for example 0.05-5mg/Kg body weight).But should understand that the accurate dosage of being taken should be according to waiting to control the character of disease and severity and patient's sex and the different of age change.
The present composition can be multiple formulation.For example, it can be tablet, capsule, solution or a suspension for oral use; The suppository that is used for rectal administration; The sterile solution or the suspension that are used for intravenous injection or intramuscularly administration; The aerosol or spray solution or the suspension that are used for inhalation; Be used to be blown into pharmaceutically acceptable solid diluent of containing of the administration powder formulation of lactose for example; Or be used for the skin patch of transdermal administration.The unitary dose of said composition should contain the pharmacy acceptable salt of 5-200mg formula I compound for example or its equivalent.
The weight percentage of present composition Chinese style I compound should be because of the different changes to some extent of route of administration.For example, said composition can contain 0.1-99.5%(weight) formula I compound or its pharmacy acceptable salt.
Said composition can make with acceptable diluent and carrier on the pharmaceutics well known in the art by conventional method.Oral tablet and capsule should be made enteric coating (as the enteric coating based on cellulose acetate phthalate) form, so that make formula I activeconstituents reduce to minimum degree with contacting of hydrochloric acid in gastric juice.
The present composition can contain also that one or more are known to cardiovascular system diseases or morbid state treatment valuable drug.So except that formula I compound, they also can contain for example known anticoagulant, prostanoid shrinking agent antagonistic (prostanoid constrictor antagonist) or synthase inhibitor (thromboxane A
2Antagonist or synthase inhibitor), cyclooxygenase-2 inhibitors, hypolipidemic, Inotropic medicament (inotropic agent) or thrombolytic agent.
Except being used for therapeutic treatment, formula I compound also can be used as the pharmacology instrument, be used for the exploitation and the demarcation of pilot system, described pilot system is the pilot system of new cardiovascalar agent being assessed about with laboratory animal such as cat, dog, rabbit, monkey, rat and mouse.
The present invention will be illustrated by following unconfined embodiment, wherein, unless other explanation is arranged:
(ⅰ) evaporation is finished through rotary evaporation in vacuo;
(ⅱ) operate in room temperature, be to carry out in the 18-26 ℃ of scope;
(ⅲ) dodge column chromatography or medium pressure liquid chromatography (MPLC) be with silica gel [Fluka Kieselgel 60(cat. no .60738) can be from Switzerland Buchs, Fluka AG. buys, or Merck Kieselgel Art.9385, can be from German Darmstadt, E Merck obtains] finish;
(ⅳ) yield only is used to illustrate, and may not be by making great efforts accessible maximum yield;
(ⅴ) proton magnetic resonance (PMR) spectrum is generally measured in 200MHz, make solvent with deuterated dimethyl sulfoxide, mark in tetramethylsilane (TMS) is done, and use with respect to TMS and represent in the chemical shift δ value of ppm (parts per million) and come the main peak of mark: s with abbreviation commonly used, unimodal; M, multiplet; T, triplet; Br, broad peak; D, double peak; Q, quartet; And
(ⅵ) all end products are all by trace analysis, and nucleus magnetic resonance and/or mass spectrum are identified.
Embodiment 1
Stirring down the N-(2-aminoethyl) morpholine (2.60g) adds in acetonitrile (200ml) suspension of 7-amino-(2-furyl)-5-methylsulfonyl-[1,2,4] triazolo [1,5-a] [1,3,5] triazine (3.36g), and continuation was stirred 2 hours.Evaporating solvent, residue is with silicon-dioxide (200g) purification by chromatography, with the methylene dichloride wash-out that contains methyl alcohol (10% v/v).The solid of separating out from ethanol (4.0g) is the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino) [1,2,4] triazolo [1,5-a] [1,3,5]-triazine-7-amine (3.03g), fusing point 242-244 ℃; Trace analysis result: C, 50.7; H, 5.40; N, 33.7%; C
14H
18N
8O
2Require:
C50.9H5.5N33.9%。
The NMR:2.47(broad peak, 6H, CH
2N(CH
2)
2), 3.43(q, 2H, CH
2NH), 3.61(m, 4H, CH
2OCH
2), 6.68(d of d, 1H, furyl-4H, 7.06(d, 1H, furyl-3H), 7.27(br, 1H, NH), 7.86(d, 1H, the and 8.15(br of furyl-5H), 2H, NH
2); M/e331(M+H)
+
Necessary raw material (reactant) is prepared as follows:
(1) hydrogen chloride gas (20.0g) is squeezed in the mixture of ice-cooled 2-chaff nitrile (46.5g) and dehydrated alcohol (23.0g).After gas added, solid was separated out from mixture.The crystallinity solid is assembled in filter, and with it in pyridine (300ml) and amino guanidine nitrate (56.0g) reflux 4 hours together.With the miscellany cooling, the filtering solid matter with the filtrate evaporation, obtains thick 3-amino-5-(2-furyl)-1,2, the 4-triazole.With this material nitric acid (400ml, 50%, V/V) processing purifying.The crystalline salt that the filter collection generates, water (100ml) and ethanol (50ml) washing successively, air-dry, obtain 3-amino-5-(2-furyl)-1,2,4-triazole nitrate (45.0g), fusing point 130-133 ℃ (decomposition).The salt (184g) that several (184.0g) is such is suspended in the hot water (400ml) and adds yellow soda ash (46.0g) in batches.To obtain 3-amino-5-(2-furyl after the basic solution cooling that obtain)-1,2,4-triazole (82.0g) is colourless prism, fusing point 204-206 ℃,
NMR6.05(s, 2H, NH
2), 6.6(s, 1H, furyl-4H), and 6.7(s, 1H, furyl-3H), and 7.7(s, 1H, furyl-5H), 12.05(br s, 1H NH).
(2) having slowly in the presence of the argon gas stream, 3-amino-5-(2-furyl)-1,2, the intimate mixture of 4-triazole (33.0g) and N-cyano group dithio iminocarbonic acid dimethyl ester (33.0g) was in 170 ℃ of heating 1 hour.After the cooling with the solid that obtains with silicon-dioxide (600g) column chromatography purifying, dichloromethane solution (5-10% V/V) wash-out with the ethyl acetate that contains continuous increment, obtain colorless solid (11.1g) 7-amino-2-(2-furyl)-5-methylthio group-[1,2,4] triazolo [1,5-a] [1,3,5] triazine, TLC identifies it is pure basically, during use without being further purified.[make above-mentioned small amount of solid recrystallization with ethanol, obtain crystal, fusing point is 238-240 ℃.Trace analysis result: C, 44.0; H, 3.3; N, 33.7; C
9H
8N
6SO.0.05C
2H
5OH requires C, 43.6; H, 3.3; N, 33.6;
NMR 1.05 and 3.4(t+q, crystalline ethanol), 2.5(s, 3H, CH
3S-), 6.7(dd, 1H, furyl-4H), 7.2(d, 1H, furyl-3H), 7.7(d, 1H, the 8.7-9.0(br d of furyl-5H), 2H, NH
2); M/e 248(M
+).
(3) with 3-chlorine peroxybenzoic acid (concentration is 50%, and dichloromethane solution 45.0g) (300ml) stirs and adds to ice-cold 7-amino-2-(2-furyl down)-5-methylthio group-[1,2,4] triazolo [1,5-a] in methylene dichloride (300ml) suspension of [1,3,5] triazines (8.0g).Discard remaining water layer, the suspension liquid temperature that obtains to room temperature, and was stirred 16 hours.With solvent evaporation, in residue, add ethanol (150ml).The suspension liquid that obtains was placed 30 minutes, rocked frequently.Filter collection solid is used washing with alcohol with it then, and drying obtains colorless solid 7-amino-2-(2-furyl)-5-methylsulfonyl-[1,2,4] triazolo [1,5-a] [1,3,5] triazines (6.6g), during use without being further purified.
NMR:3.3(s, 3H), CH
3.SO
2), 6.7(q, 1H, the 7.3(q of furyl-4H), 1H, furyl-3H), and 7.9(q, 1H, furyl-5H), 9.4-9.8(d, 2H, NH
2), |
Embodiment 2
With 7-amino-2-(2-furyl)-5-phenoxy group-[1,2,4] triazolo [1,5-a] [1,3,5] triazine (1.47g) and N-(2-aminoethyl) mixture of morpholine (0.78g) reflux 48 hours in propyl alcohol (75ml) shows that up to thin-layer chromatography reaction carries out fully on basic.Remove and desolvate, residue is with silicon-dioxide chromatography purifying, with containing 10%(V/V) the dichloromethane solution wash-out of methyl alcohol, the solid alcohol crystal that obtains, get the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine (0.69g) is fusing point 243-246 ℃, identical with resulting product among the embodiment 1 in all respects.
Necessary raw material can be by following preparation:
Hexamethyldisiloxane (3.0mol) is added to Vanadium Pentoxide in FLAKES (1.5 moles are determined as P
4O
10) the dimethylbenzene slurries in.With mixture heating up to 90 ℃, keep then above 1.5 hours.In 90 ℃ of stirrings one hour, solids all during this all dissolved then.Then with N-2-(4,6-two phenoxy groups) [1,3,5] triazinyl)-N '-(2-furoyl) hydrazine (1.0mol) adds in this solution, is warming up to backflow.The solid dissolving, but in the crystallization process, second kind of solid precipitation comes out.When mixture was cooled to 25 ℃, crystallization carried out for simplicity, can placing and spending the night fully usually in 2.5 hours.Add acetonitrile then and cool the temperature to 15 ℃.Add water, mixture is cooled to 15 ℃ again, add 0.91 ammonia solution, maintain the temperature at below 25 ℃.Once finish, be warmed up to 40 ℃ one hour.Reaction mixture is cooled to 25 ℃ then, leaches solid, and with a large amount of water washings.Yield is about 85%.
Required N-2-(4,6-two phenoxy groups) being prepared as follows of [1,3,5] triazinyl-N '-(2-furoyl) hydrazine:
With 2,4, dimethylbenzene (60ml) vlil of 6-triple phenoxyl-1,3,5-triazines (7.2g) and 2-furoyl hydrazine (2.5g) 3 hours.Except that desolvating, residue with methylene chloride (2-3% V/V) wash-out, is used the Virahol crystallization with silica gel (400g) chromatography purification by evaporation, obtain N-2-(4,6-two phenoxy groups) [1,3,5] triazinyl-N '-(2-furoyl) hydrazine is colourless prism, fusing point 182-184 ℃; Trace analysis result: C, 61.4; H, 3.8; N, 17.7%; C
20H
15N
5O
4Require C, 61.7; H, 3.9; N, 18.0%;
The d of NMR 6.63(d, 1H, 4-furyl H), 7.05-7.5(complexity, 1H, 3-furyl H and phenyl H) and, 7.87(s, 1H, 5-furyl H), 9.96(s, 1H, NH) and 10.34(s, 1H, NH); M/e 390(M+H)
+
Embodiment 3
With the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine (14.2g) is dissolved in the hot methanol (1400ml) and with the hydrogenchloride De dioxane solution of 7N it is acidified to pH3.Mixture was kept under the condition of pH3 30 minutes.Evaporating solvent changes solvent into fresh methyl alcohol, then evaporation.Repeat this process more than twice.
Residue is with methyl alcohol (80ml) recrystallization, under 80 ℃/vacuum condition dry 16 hours then, obtains the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine dihydrochloride (15.6g).Fusing point 313-315 ℃ (decomposition).Trace analysis result: C 39.6; H, 5.4; N, 26.6; Cl, 15.9; H
2O, 5.1%; C
14H
18N
8O
2-2HCl-1.2H
2O-0.05 CH
3OH requires: C, 39.57; H, 5.34; N, 26.27; Cl, 16.63; H
2O, 5.06%; MS331(M+H).NMR: in room temperature because the existence of rotational isomer makes spectrum very complicated,
373
OK δ 3.3(m, 6H, 3xCH
2N); 3.75(t, 2H, CH
2NH); 3.9(t, 4H, CH
2OCH
2); 6.65(m, 1H, furyl-4H); 7.09(d, the 1H furyl-3H); 7.5(brs, 1H, NHCH
2); 7.8(d, 1H, furyl-5H); 8.0(brs, 2H, NH
2); Also at δ 3.2(s, crystalline methyl alcohol).
Embodiment 4
Below illustrate representational pharmaceutical dosage form, they contain formula I compound or its pharmacy acceptable salt (hereinafter being expressed as " compounds X "), are used for treatment or prevention to the people:
(a) tablet mg/ sheet
Compounds X 5.0
Lactose Ph, Eur 233.75
Croscarmellose sodium 6.0
W-Gum 15.0
Polyvinylpyrrolidone (5% W/V, pasty state) 2.25
Magnesium Stearate 3.0
(b) capsule mg/ capsule
Compounds X 10
Lactose ph, Eur 488.5
Magnesium Stearate 1.5
Above-mentioned preparation can make by the ordinary method of knowing in the pharmacy field.Tablet can be enteric coated with ordinary method, for example available cellulose acetate phthalate dressing.
Chemical formula
Chemical formula
Chemical formula
Claims (7)
1,2-(2-furyl)-5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine and pharmacy acceptable salt thereof.
2, salt as claimed in claim 1, it is selected from the salt that forms with following acid: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, methylsulfonic acid, trifluoroacetic acid, oxalic acid, citric acid or toxilic acid.
3, compound as claimed in claim 1, it is selected from the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine and 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine dihydrochloride.
4, compound as claimed in claim 1, it is the 2-(2-furyl)-the 5-[2-morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine.
5,2-(2-furyl)-and the 5-[2-(morpholino) ethylamino] preparation method of [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine or its pharmacy acceptable salt, it comprises:
(a) with formula II compound and N-(2-aminoethyl) morpholine or its reactant salt, the structure of described formula II compound is as follows:
The suitable leavings group of Z representative in the formula;
(b) with following formula IX compound and morpholine reaction:
Z in the formula
1Represent suitable leavings group;
(c) with following formula X compound and ammonia react:
Z in the formula
2Represent suitable leavings group;
(d) following formula XII compound is dewatered:
When the needs pharmacy acceptable salt, then make salt.
6, a kind of medicinal compositions, it contains the 2-(2-furyl)-the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine or its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier.
7,2-(2-furyl)-and the 5-[2-(morpholino) ethylamino] [1,2,4] triazolo [1,5-a] [1,3,5] triazine-7-amine or the purposes of its pharmacy acceptable salt aspect drug manufacture, described medicine is used for the treatment of ischemic heart disease, peripheral vascular disease, or cerebral ischaemia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9226735.0 | 1992-12-22 | ||
| GB929226735A GB9226735D0 (en) | 1992-12-22 | 1992-12-22 | Azole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1093708A true CN1093708A (en) | 1994-10-19 |
Family
ID=10727043
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93121279A Pending CN1093708A (en) | 1992-12-22 | 1993-12-22 | Pyrrole derivative |
Country Status (9)
| Country | Link |
|---|---|
| CN (1) | CN1093708A (en) |
| AP (1) | AP9300596A0 (en) |
| AU (1) | AU5656494A (en) |
| GB (2) | GB9226735D0 (en) |
| HR (1) | HRP931512A2 (en) |
| IL (1) | IL107876A0 (en) |
| SI (1) | SI9300674A (en) |
| WO (1) | WO1994014812A1 (en) |
| ZA (1) | ZA939045B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329388C (en) * | 2002-05-30 | 2007-08-01 | 索尔瓦药物有限公司 | 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors |
| CN112500416A (en) * | 2019-07-30 | 2021-03-16 | 杭州阿诺生物医药科技有限公司 | Preparation method of pyrazolotriazine compound intermediate |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2639299A (en) * | 1998-02-24 | 1999-09-15 | Kyowa Hakko Kogyo Co. Ltd. | Remedies/preventives for parkinson's disease |
| US6355653B1 (en) | 1999-09-06 | 2002-03-12 | Hoffmann-La Roche Inc. | Amino-triazolopyridine derivatives |
| US6506772B1 (en) | 2000-12-15 | 2003-01-14 | Hoffmann-La Roche Inc. | Substituted [1,2,4]triazolo[1,5a]pyridine derivatives with activity as adenosine receptor ligands |
| US6514989B1 (en) * | 2001-07-20 | 2003-02-04 | Hoffmann-La Roche Inc. | Aromatic and heteroaromatic substituted 1,2,4-triazolo pyridine derivatives |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0459702A1 (en) * | 1990-05-29 | 1991-12-04 | Zeneca Limited | Azole Derivatives |
-
1992
- 1992-12-22 GB GB929226735A patent/GB9226735D0/en active Pending
-
1993
- 1993-11-26 GB GB939324349A patent/GB9324349D0/en active Pending
- 1993-12-02 ZA ZA939045A patent/ZA939045B/en unknown
- 1993-12-02 AP APAP/P/1993/000596A patent/AP9300596A0/en unknown
- 1993-12-03 IL IL10787693A patent/IL107876A0/en unknown
- 1993-12-10 AU AU56564/94A patent/AU5656494A/en not_active Abandoned
- 1993-12-10 WO PCT/GB1993/002525 patent/WO1994014812A1/en active Application Filing
- 1993-12-21 HR HR931512A patent/HRP931512A2/en not_active Application Discontinuation
- 1993-12-22 SI SI9300674A patent/SI9300674A/en unknown
- 1993-12-22 CN CN93121279A patent/CN1093708A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1329388C (en) * | 2002-05-30 | 2007-08-01 | 索尔瓦药物有限公司 | 1,3,5-triazine derivatives as ligands for human adenosine-A3 receptors |
| CN112500416A (en) * | 2019-07-30 | 2021-03-16 | 杭州阿诺生物医药科技有限公司 | Preparation method of pyrazolotriazine compound intermediate |
| CN112500416B (en) * | 2019-07-30 | 2021-12-17 | 厦门宝太生物科技股份有限公司 | Preparation method of pyrazolotriazine compound intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1994014812A1 (en) | 1994-07-07 |
| GB9226735D0 (en) | 1993-02-17 |
| GB9324349D0 (en) | 1994-01-12 |
| ZA939045B (en) | 1994-06-22 |
| SI9300674A (en) | 1994-06-30 |
| AU5656494A (en) | 1994-07-19 |
| IL107876A0 (en) | 1994-04-12 |
| HRP931512A2 (en) | 1994-12-31 |
| AP9300596A0 (en) | 1994-01-31 |
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